Optimized diazo scaffold for protein esterification.

†Department of Biochemistry and ‡Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.

Abstract

The O-alkylation of carboxylic acids with diazo compounds provides a means to esterify carboxylic acids in aqueous solution. A Hammett analysis of the reactivity of diazo compounds derived from phenylglycinamide revealed that the (p-methylphenyl)glycinamide scaffold has an especially high reaction rate and ester/alcohol product ratio and esterifies protein carboxyl groups more efficiently than any known reagent.

Diazo compounds have another well-known mode of reactivity—esterification of carboxylic acids. We realized that this reactivity could provide unique opportunities in chemical biology. For example, unlike the alkylation of other functional groups, O-alkylation of a carboxyl group is bioreversible because mammalian cells contain non-specific esterases. The esterification of carboxyl groups in proteins and other biomolecules is, however, difficult to effect, as solvent water competes effectively with alcohols for eletrophilic acyl groups. In contrast, esterification reactions mediated by diazo groups rely on the carboxyl group serving as a nucleophile ().